Skeletal muscle fibrosis is a phenomenon which frequently occurs in diseased or damaged muscle. It is characterized by the excessive growth of fibrous tissue which usually results from the body's attempt to recover from injury. Fibrosis impairs muscle function and causes weakness. The amount of muscle function loss generally increases with the extent of fibrosis. Often fibrosis is progressive and can contribute to the patient's inability to carry out ordinary tasks of independent living, such as grasping objects or walking.
Victims of muscular dystrophies, particularly Becker muscular dystrophy (BMD) and the more severely penetrating allelic manifestation, Duchenne muscular dystrophy (DMD), frequently suffer from increasing skeletal muscle fibrosis as the disease progresses. BMD patients usually exhibit progressive muscle weakness and wasting. The advance of fibrosis often causes ever greater loss of mobility and a reduced life expectancy. At some point, the patient may become too weak to walk and takes to a wheelchair. Victims of DMD typically lose the ability to walk by their early teen years and experience tragically premature death before the age of twenty. DMD patients typically succumb to cardio-pulmonary complications which may be partly attributable to strain associated with fibrosis-induced muscle function loss and weakness.
Other afflictions such as denervation atrophy are known to produce skeletal muscle fibrosis. Denervation atrophy is a degradation of muscle tissue caused by loss of neural contact to a muscle. The lost neural contact can be due to trauma, for example by accidentally severing a nerve. Neuromuscular disease can produce a similar effect. For example, acute polyneuritis, poliomyelitis, Werdig/Hoffman disease, amyotrophic lateral sclerosis, also known as Lou Gehrig's Disease, and progressive bulbar atrophy disease, are known to cause denervation atrophy. Generally, denervated muscle fibers progressively degrade at a rate such that about 75% muscle mass reduction and about 10% muscle volume reduction occur within 120 days of the denervating event. Unless the muscle is re-innervated, which is not generally possible in the case of many neuromuscular disease induced denervating atrophies, skeletal muscular fibrosis normally ensues. Such fibrosis routinely continues to develop and produces muscle function impairment with debilitating effects similar to those described above, as reported by Astrom, K. E., and Adams, R. D., Disorders of Voluntary Muscle, 5th edition., Churchill Livingstone, N.Y. (1995), pp. 157-161.
Retarding the fibrosis growth rate should slow the loss of muscle function, thereby postponing onset of wheelchair dependence and other adverse consequences suffered by DMD and BMD patients. Reducing skeletal muscular fibrotic tissue growth associated with muscle damage and disease ought to ameliorate the loss of muscle function, thereby enhancing the patient's quality of life. Heretofore, medical science has been unsuccessful at producing a safe, pharmaceutical treatment to reduce skeletal muscle fibrosis. That is, no treatment which affects fibrotic tissue but does not adversely affect healthy muscle tissue or other body functions is currently known. Consequently, a pharmaceutical therapy which prevents or retards the build up of skeletal muscle fibrosis that accompanies disorders such as Duchenne and Becker muscular dystrophies is desirable.
Accordingly, it is an object of the present invention to provide a method of reducing or preventing the progressive build up of fibrotic tissue in diseases characterized by skeletal muscle fibrosis.
Another object of this invention is to provide a treatment capable of prolonging the start of immobility and reducing the severity of other symptoms caused by skeletal muscular fibrosis associated with Duchenne and Becker muscular dystrophies.
It is still another object of this invention to provide a treatment to lessen the debilitating effects of fibrosis brought on by other disorders, such as denervation atrophy.
It is a further objective of this invention to provide a pharmaceutical treatment for skeletal muscle fibrosis which is safely and easily administered by conventional routes and has minimal adverse side effects.